Variable intrinsic sensitivity of human tumor cell lines to raltitrexed (Tomudex) and folylpolyglutamate synthetase activity.

Abstract:

:The cytotoxic effects of Tomudex (TX) were investigated on a panel of 15 human tumor cell lines expressing a spontaneous sensitivity to the tested agent. We determined the basal cellular amount of relevant cellular factors potentially related to the cytotoxic efficacy of or resistance to TX. We selected thymidylate synthase (TS) as the target for TX, basal reduced folates (RF), because RF may compete with TX for a common site on the TS molecule. We also tested folylpolyglutamate synthetase (FPGS) because this is the enzyme which transforms the drug into its active polyglutamated form. Results were as follows. There was a wide inter-cell line variability in IC50 values for TX and there were marked differences between cell lines for all tested biochemical parameters. No link was observed between basal cellular TS activity and TX cytotoxic efficacy. There was an inverse relationship between reduced folate cellular content and TX IC50 values; this relationship did not, however, reach statistical significance. The only significant relationship was found between basal cellular FPGS activity and TX IC50r = -0.56, p = 0.03. Tumor cells with a relatively high FPGS activity were more sensitive to TX cytotoxic effects and vice versa. Along with previous results which showed that acquired resistance to TX is accompanied by a decrease in FPGS activity, the present data are strongly indicative of a prominent role played by FPGS activity in the intrinsic sensitivity to TX. Means to up-regulate FPGS activity with pharmacological or tumor-specific genetic approaches are recommended so as to optimize TX antitumor activity.

journal_name

Anticancer Drugs

journal_title

Anti-cancer drugs

authors

Chéradame S,Chazal M,Fischel JL,Formento P,Renée N,Milano G

doi

10.1097/00001813-199906000-00010

subject

Has Abstract

pub_date

1999-06-01 00:00:00

pages

505-10

issue

5

eissn

0959-4973

issn

1473-5741

journal_volume

10

pub_type

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